Called mTOT (for mitochondrial target of thiazolidinediones), the drug target is a cellular protein complex through which new anti-diabetic drugs exert their insulin-sensitizing effects.

In a nutshell, insulin sensitizers improve
the way insulin works. And insulin is the hormone used to treat
diabetes by controlling the amount of sugar that is in the blood.

"What this is is a complex of proteins in the mitochondrial membrane that
hasn't been studied before and we found them by creating a special probe,"
said Jerry Colca, chief scientific officer of Metabolic Solutions.

He likened that to trying to unravel a big jumbled ball of string by first finding the
end of the string.

"This (the protein complex) is a handle that lets us get at what's going on
here," he said.

On Wednesday, Metabolic Solutions published data on the new drug target in PLOS ONE,
an open-access, online scientific publication. PLOS ONE features
reports of original research in science and medicine. It has
headquarters in the United States and the United Kingdom – in San
Francisco and Cambridge, respectively.

"This is the first published result identifying this target and this protein," Colca said.

Once research is published, it is reviewed by other scientists, and Colca said, "It is not real until it gets published."

Recently published second-phase clinical data from a study involving 258 type 2diabetic patients, indicate that modulating mTOT "could constitute a new approach for the discovery and development of potentially more useful and novel insulin sensitizers," the company reports.

MSDC-0160 was studied in the Phase 2b
clinical trail. It was a 90-day, randomized, double-blind study
completed in December 2011.

“Data suggest mTOT functions as a molecular sensor switch that coordinates carbohydrate, lipid, and amino acid metabolism with cell function,” according to information provided by Metabolic Solutions, which has been working on drug compounds that perform without side-effects commonly associated with insulin sensitizers that are already in use. Those side-effects include weight gain, fluid retention, bone loss and congestive heart failure.

“The only drug that attacks both insulin resistance and beta cell
dysfunction, the root causes of type 2 diabetes, is an insulin
sensitizer,” Dr. Ralph A. DeFronzo said in a press release.

He is
professor of medicine and of the Diabetes Division at the University of
Texas Health Science Center and the Audie L. Murphy Memorial VA
Hospital in San Antonio, Texas.

“There is a growing interest in a
new generation of insulin sensitizers that appear to bind to proteins
in the mTOT complex, but not activate the PPARγ receptor (nuclear
receptor proteins) at therapeutic doses,” DeFronzo said. “As such, these
new therapeutic agents likely will not elicit the side effects
associated with currently approved insulin sensitizers.”

It is now generally accepted that activating PPARy causes the side-effects with this class of compounds. That has limited the use of
current drugs and prevented the development of new insulin-sensitizing
agents, according to information provided by Metabolic Solutions.

"With the discovery of the mTOT complex, researchers now have a clear
path forward to create new, more useful insulin sensitizers," according
to a statement by the company.

The mTOT discovery team was led by Ph.D researchers Colca and Rolf Kletzien,
both of Kalamazoo. They are former Pharmacia/Pfizer Inc. scientists who
are considered to be among the original researchers in the field of
insulin sensitizers. They founded Metabolic Solutions in 2006. The company now has 14 workers.

The
company stated that the new drug target may also play a role in helping
treat other diseases of aging such as Alzheimer’s disease and
Parkinson’s disease. In February, Metabolic Solutions received funding from The Michael J. Fox Foundation for
Parkinson's Research to conduct preclinical research on MSDC-0160, as a potential treatment for involuntary tics and movements associated with the disease (levodopa-induced dyskinesia).

Metabolic Solutions Development Co. LLC is one of the cluster of life-science companies formed in greater Kalamazoo after Pfizer Inc. acquired Pharmacia Corp. in 2003 and down-sized, shedding dozens of individuals with backgrounds in pharmaceutical work and scientific research.

It and many other life-sciences companies (those working on technologies and treatments to improve human health care) are located at the Southwest Michigan Innovation Center, an incubator for such companies at Western Michigan University's Business Technology and Research Park, south of Parkview Avenue and Drake Road.

Diabetes is a condition that can cause cardiovascular disease, chronic renal failure and other maladies is not properly treated. It is estimated affect 340 million people world-wide, including about 26 million adults and children in the United States.